Paclitaxel is an alkaloid extracted from the bark of a yew, which promotes the formation of microtubules from tubulin dimmers. It is also used as an antimicrotubule agent stabilizing the microtubules by preventing depolymerization, which shows superior anti-cancer effect against ovarian cancer, breast cancer, head and neck cancer and non-small cell lung cancer.
Since the above paclitaxel has a very low solubility against water, 30 μg/ml, and is physically unstable, research on paclitaxel is being performed. Especially, due to its non-solubility, it is difficult for it to be used as an injection. Further, the paclitaxel injection has various problems such as low stability and toxicity caused by solubilizer, and various researches are being performed to overcome such problems.
Prior art discloses a method [PCT/AU93/00599] for preparing a solution whose pH is lower than 8.1 by adding organic acid to paclitaxel in order to enhance drug stability. However, since the solubilizer used in this method, polyoxyethyleneglycerol triricinolate, Cremophor EL™ (hereinafter referred to as “Cremophor EL”), causes a serious hypersensitive reaction and separates plasticizer from polyvinyl chloride resin set, it is not preferable to be used as an injection.
Hereupon, in order to solve such problems, the use of a liposome formulation prepared by using phosphatidylcholine as a solubilizer has excluded the use of Cremophor EL™, but still, the low solubility (0.8 mg/ml) has not been improved and the stability of the above liposome formulation is being questioned, and thus, there is difficulty in mass production [Pharm. Res., 1994, 11(2), 206–212; Pharm. Res., 1994, 11(6), 889–896].
Recently, researches on improving solubility by chemically combining paclitaxel with a biodegradable block copolymer comprising hydrophilic region and hydrophobic region, as a solubilizer are actively being performed, but this method has difficulty in being used as a drug due to the polymerization of the two hydrophobic and hydrophilic regions, the difficulty such as evaporation and freeze drying process during the manufacturing process, and the accompanying increase of the production cost and the decrease of biocompatibility [JP 116,082/89; JP 206,815/94; EP 0 583 955 A2].
A preparation marketed in the name of Taxol® is disclosed, which is a liquid preparation wherein 30 mg of paclitaxel is dissolved in 5 ml of a mixed solution of absolute alcohol/Cremophor EL™ (1:1). When being administered, the solution is diluted with physiological saline or 5% glucose solution to 0.6–1.2 mg/ml and only 175 mg/m2 is instilled and administered into the veins throughout 6–24 hours. However, Cremophor EL™ which is used as the above solubilizer contains toxicity itself which causes serious toxicities such as hypersensitivity, dyspnea and flushing. Thus, in order to minimize the hypersensitive reactions which are side effects caused when taxol is administered, adrenocortical hormone(Dexamethasone), antihistimines(Diphenhydramine) and H2 antagonist(Cimetidine) are administered in advance. Further, due to the problem that titer declines by paclitaxel degradation caused by the decrease of formulation stability, it is required to be stored at a low temperature. Also, various side effects are being reported such as the fact that it must go through a filtering progress when being administered in human body since particles are generated with the progress of time.
Hereupon, in order to overcome the above problems, the present inventors studied injectable compositions of paclitaxel comprising low toxic solubilizer and stabilizer, and thus, found out that polyoxyl hydrogenated castor oil is used as a solubilizer, and N-acetyl amino acid is used as a stabilizer to prepare injectable compositions of paclitaxel containing absolute alcohol. Further, the present inventors completed the invention by finding out that the compositions of the present invention shows more than the same pharmaceutical effects compared with the known injectable compositions of paclitaxel, and that the drug stability increases at room temperature, and that toxicity decreases.